The primary objectives of the proposed studies are to characterize the drug-drug interactions of a series of model centrally-acting drugs in the morphine-dependent rat and to investigate the mechanisms by which such interactions are manifested. Previous work in our laboratory has shown that the pharmacological response to both hexobarbital and amphetamine is enhanced in the morphine-dependent rat. The reason for the increased response has been shown to be due, in part, to changes in brain sensitivity and alterations of hepatic metabolism of the drugs. Experiments will be undertaken to characterize further the pharmacological response following the administration of d-amphetamine, cocaine, diazepam, ethanol, methaqualone, or pentobarbital. Studies to elucidate the underlying mechanism for observed alterations in pharmacological response in the morphine-dependent rat will include effects on brain sensitivity, effects on disposition of the drug to the brain, and effects on elimination of the drug from the body. The results of these studies will lead to a more meaningful understanding of certain of the clinical symptoms observed in both humans and animals following the administration of drugs to the morphine-dependent species.